Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies

Bart Van Wijmeersch, Barry A Singer, Aaron Boster, Simon Broadley, Óscar Fernández, Mark S Freedman, Guillermo Izquierdo, Jan Lycke, Carlo Pozzilli, Basil Sharrack, Brian Steingo, Heinz Wiendl, Sibyl Wray, Tjalf Ziemssen, Luke Chung, David H Margolin, Karthinathan Thangavelu, Patrick Vermersch, Bart Van Wijmeersch, Barry A Singer, Aaron Boster, Simon Broadley, Óscar Fernández, Mark S Freedman, Guillermo Izquierdo, Jan Lycke, Carlo Pozzilli, Basil Sharrack, Brian Steingo, Heinz Wiendl, Sibyl Wray, Tjalf Ziemssen, Luke Chung, David H Margolin, Karthinathan Thangavelu, Patrick Vermersch

Abstract

Background: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.

Objective: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).

Methods: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.

Results: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%).

Conclusion: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.

Clinicaltrials.gov registration numbers: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Keywords: Alemtuzumab; disability; disease-modifying therapy; efficacy; magnetic resonance imaging (MRI); relapsing–remitting multiple sclerosis (MS).

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.V.W. received research and travel grants; honoraria for MS-expert advice; and speakers’ fees from Actelion, Bayer Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva. B.A.S. received fees for speaking and/or consulting from AbbVie, Acorda, Biogen, EMD Serono, Genentech, Novartis, Pfizer, Roche, Sanofi, and Teva and research support from AbbVie, Acorda, Alkermes, Biogen, MedImmune, Novartis, Roche, and Sanofi. A.B. received consulting fees and/or fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. S.B. received speaking and/or consulting fees from Bayer, Biogen, Merck Serono, Novartis, Roche, and Sanofi. O.F. received speaking and/or consulting fees from Allergan, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi, and Teva; compensation for serving as a journal editor, associate editor, or member of an editorial advisory board for Revista Española de Esclerosis Múltiple; and research support from the Hospital Foundatión FIMABIS. M.S.F. received honoraria/consulting fees from Actelion, Bayer, Biogen, Canada Innovation, Chugai, EMD Canada, Merck Serono, Novartis, Roche, Sanofi, and Teva; support as a member of advisory board, board of directors, or other similar group from Actelion, Bayer, Biogen, Clene, Merck Serono, Novartis, Roche, and Sanofi; and fees for participation in speaker’s bureau from Sanofi. G.I. received speaking and advisory fees from Almirall, Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva. J.L. received travel support and/or lecture honoraria from Biogen, Novartis, Sanofi, and Teva; support from scientific advisory boards from Almirall, Biogen, Novartis, Sanofi, and Teva; compensation as part of the editorial board for Acta Neuro-logica Scandinavica; and unconditional research grants from Biogen, Novartis, and Teva. C.P. received consulting and/or speaking fees, research, and travel grants from Actelion, Biogen, Merck, Novartis, Sanofi, and Teva. B. Sharrack received research and travel grants; honoraria for expert advice on MS; and speaker’s fees from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. B. Steingo received consulting; speaking fees; and/or grant/research support from Acorda, Biogen, EMD Serono, Mallinckrodt, Novartis, Sanofi, and Teva. H.W. received consulting and/or speaking fees and grant/research support from Bayer, Bayer Schering Pharma, Biogen, Elan Corporation, Lilly, Lundbeck, Merck Serono, Novartis, Novo Nordisk, Sanofi, and Teva Neuroscience. S.W. received fees as consultant; principal investigator; and/or speaker from Alkermes, Asclepios, Biogen, Celgene, EMD Serono, Novartis, Roche, Sanofi, and TG Therapeutics. T.Z. received consulting and/or speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva and grant/research support from Biogen, Novartis, Sanofi, and Teva. L.C. and K.T. receive compensation as employees of Sanofi. D.H.M. received compensation as an employee of Sanofi at the time this study was conducted and is currently an employee of Cerevance, Inc. P.V. received consulting and/or speaking fees and research support from Almirall, Bayer, Biogen, Celgene, Merck Serono, Novartis, Sanofi, Servier, and Teva.

Figures

Figure 1.
Figure 1.
Proportions of early relapsers and early non-relapsers. Proportions of patients with and without relapse between alemtuzumab Courses 1 and 2 in the core CARE-MS I (left) and CARE-MS II (right) studies. CARE-MS: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis.
Figure 2.
Figure 2.
Clinical efficacy outcomes in early relapsers through 6 years. (a) ARR and proportions free of relapse, (b) proportions free of 6-month CDW, and (c) proportions achieving 6-month CDI over 6 years in patients with relapse between alemtuzumab Courses 1 and 2 in the core CARE-MS I and CARE-MS II studies. ARR: annualized relapse rate; CARE-MS: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CDI: confirmed disability improvement; CDW: confirmed disability worsening; CIs: confidence intervals; EDSS: Expanded Disability Status Scale. Error bars denote 95% CIs. aKaplan–Meier estimates. bNumber at risk is the number of patients who remained on study and had yet to experience 6-month CDW or 6-month CDI. CDI is defined as ⩾1-point EDSS decrease from baseline confirmed over 6 months (CDI is assessed only in patients with baseline EDSS score ⩾ 2.0). CDW is defined as ⩾1-point EDSS increase (or ⩾1.5 points if baseline EDSS = 0) confirmed over 6 months.
Figure 3.
Figure 3.
MRI outcomes in early relapsers through 6 years. (a) Proportions free of MRI disease activity and (b) median percentage yearly change in BPF over 6 years in patients with relapse between alemtuzumab Courses 1 and 2 in the core CARE-MS I and CARE-MS II studies. Freedom from MRI disease activity was defined as the absence of new gadolinium-enhancing T1 and new/enlarging T2 hyperintense lesions. BPF: brain parenchymal fraction; CARE-MS: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CIs: confidence intervals; MRI: magnetic resonance imaging. Error bars denote 95% CIs.
Figure 4.
Figure 4.
Efficacy outcomes of early relapsers and early non-relapsers through Year 6. (a) ARR during Year 6, (b) proportions free of 6-month CDW over 6 years, (c) proportions achieving 6-month CDI over 6 years, (d) proportions free of MRI disease activity during Year 6, and (e) median percentage change in BPF during Year 6 in patients with and without relapse between alemtuzumab Courses 1 and 2 in the core CARE-MS I and CARE-MS II studies. Freedom from MRI disease activity was defined as the absence of new gadolinium-enhancing T1 and new/enlarging T2 hyperintense lesions. ARR: annualized relapse rate; BPF: brain parenchymal fraction; CARE-MS: Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CDI: confirmed disability improvement; CDW: confirmed disability worsening; MRI: magnetic resonance imaging; CI: confidence interval; EDSS: Expanded Disability Status Scale. Error bars denote 95% CIs. aKaplan–Meier estimates. bNumber at risk is the number of patients who remained on study and had yet to experience 6-month CDW or 6-month CDI, respectively. CDI is defined as ⩾1-point EDSS decrease from baseline confirmed over 6 months (CDI is assessed only in patients with baseline EDSS score ⩾ 2.0). CDW is defined as ⩾1-point EDSS increase (or ⩾1.5 points if baseline EDSS = 0) confirmed over 6 months.

References

    1. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380(9856): 1819–1828.
    1. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380(9856): 1829–1839.
    1. Giovannoni G, Cohen JA, Coles AJ, et al. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients. Neurology 2016; 87(19): 1985–1992.
    1. Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. Neurology 2017; 89: 1117–1126.
    1. Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy. Neurology 2017; 89: 1107–1116.
    1. Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: An update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10(10): 343–359.
    1. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35(11): 3332–3342.
    1. Hu Y, Turner MJ, Shields J, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128(2): 260–270.
    1. Wiendl H, Bourdette D, Ciccarelli O. Can immune reprogramming with alemtuzumab induce permanent remission in multiple sclerosis. Neurology 2017; 89(11): 1098–1100.
    1. Wray S, Havrdova E, Snydman DR, et al. Infection risk with alemtuzumab decreases over time: Pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Mult Scler 2019; 25(12): 1605–1617.
    1. LEMTRADA [Summary of Product Characteristics], 2019. Diegem; Belgium: Sanofi Belgium.
    1. Phelps R, Winston JA, Wynn D, et al. Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis. Mult Scler 2019; 25(9): 1273–1288.
    1. Cuker A, Bass AD, Nadj C, et al. Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management. Mult Scler. Epub ahead of print 20 February 2019. DOI: 10.1177/1352458518816612.
    1. LEMTRADA® (alemtuzumab) injection for intravenous use [prescribing information], 2019. Cambridge, MA: Genzyme Corporation.
    1. Sanofi-Aventis. LEMTRADA® (alemtuzumab) Australian product information, 2018, (accessed 17 December 2018).
    1. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415.
    1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354(9): 899–910.
    1. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–923.
    1. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop. World J Clin Cases 2015; 3(7): 545–555.
    1. Hesse D, Krakauer M, Lund H, et al. Breakthrough disease during interferon-[beta] therapy in MS: No signs of impaired biologic response. Neurology 2010; 74(18): 1455–1462.
    1. Kalincik T, Manouchehrinia A, Sobisek L, et al. Towards personalized therapy for multiple sclerosis: Prediction of individual treatment response. Brain 2017; 140(9): 2426–2443.
    1. Laroni A, Gandoglia I, Solaro C, et al. Clinical baseline factors predict response to natalizumab: Their usefulness in patient selection. BMC Neurol 2014; 14: 103.
    1. Giuliani M, Logoteta A, Prosperini A, et al. Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis. Mult Scler Demyelinating Disord 2017; 2: 10.
    1. Tremlett H, Zhao Y, Joseph J, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 2008; 79(12): 1368–1374.
    1. Popescu V, Agosta F, Hulst HE, et al. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013; 84(10): 1082–1091.
    1. Huhn K, Bayas A, Doerck S, et al. Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: A multi-center observational study. J Neurol 2018; 265(7): 1521–1527.
    1. Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2017; 4(2): e320.
    1. Berger T, Elovaara I, Fredrikson S, et al. Alemtuzumab use in clinical practice: Recommendations from European multiple sclerosis experts. CNS Drugs 2017; 31(1): 33–50.

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